Neuropathology and applied neurobiology
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Neuropathol. Appl. Neurobiol. · Jun 2012
ReviewReview: personalized mice: modelling the molecular heterogeneity of medulloblastoma.
Medulloblastoma, the most common malignant paediatric brain tumour, is thought to arise from mutations in progenitors or stem cells in the cerebellum. Recent molecular analyses have highlighted the heterogeneity of these tumours, and demonstrated that they can be classified into at least four major subtypes that differ in terms of gene expression, genomic gains and losses, epidemiology and patient outcome. Along with analysis of human tumours, a variety of animal models of medulloblastoma have been developed using transgenic and knockout technology as well as somatic gene delivery. ⋯ But the degree to which current models recapitulate the heterogeneity of the human disease remains unclear. Here we review the recent literature on the genomics of medulloblastoma and discuss the relationship of mouse models to the subtypes of the disease. Judicious use of existing models, and generation of additional models for poorly studied subtypes of medulloblastoma, will increase our understanding of tumour biology and allow evaluation of novel approaches to treatment of the disease.
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Neuropathol. Appl. Neurobiol. · Feb 2012
ReviewThe neuropathology, pathophysiology and genetics of multiple system atrophy.
Multiple system atrophy (MSA) is an unrelenting, sporadic, adult-onset, neurodegenerative disease of unknown aetiology. Its clinically progressive course is characterized by a variable combination of parkinsonism, cerebellar ataxia and/or autonomic dysfunction. Neuropathological examination often reveals gross abnormalities of the striatonigral and/or olivopontocerebellar systems, which upon microscopic examination are associated with severe neuronal loss, gliosis, myelin pallor and axonal degeneration. ⋯ These are the hallmark neuropathological lesion of MSA and are thought to play a central role in the pathogenesis of the disease. In this review, neuropathological features of MSA are described in detail, along with recent advances in the pathophysiology and genetics of the disease. Our current knowledge of the expression and accumulation of α-synuclein, and efforts to model the disease in vitro and in vivo, are emphasized in this paper and have helped formulate a working hypothesis for the pathogenesis of MSA.
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Neuropathol. Appl. Neurobiol. · Oct 2011
ReviewReview: Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates.
Professional boxers and other contact sport athletes are exposed to repetitive brain trauma that may affect motor functions, cognitive performance, emotional regulation and social awareness. The term of chronic traumatic encephalopathy (CTE) was recently introduced to regroup a wide spectrum of symptoms such as cerebellar, pyramidal and extrapyramidal syndromes, impairments in orientation, memory, language, attention, information processing and frontal executive functions, as well as personality changes and behavioural and psychiatric symptoms. Magnetic resonance imaging usually reveals hippocampal and vermis atrophy, a cavum septum pellucidum, signs of diffuse axonal injury, pituitary gland atrophy, dilated perivascular spaces and periventricular white matter disease. ⋯ Molecular studies suggested that TBIs increase the neurotoxicity of the TAR DNA-binding protein 43 (TDP-43) that is a key pathological marker of ubiquitin-positive forms of frontotemporal dementia (FTLD-TDP) associated or not with motor neurone disease/amyotrophic lateral sclerosis (ALS). Similar patterns of immunoreactivity for TDP-43 in CTE, FTLD-TDP and ALS as well as epidemiological correlations support the presence of common pathogenetic mechanisms. The present review provides a critical update of the evolution of the concept of CTE with reference to its neuropathological definition together with an in-depth discussion of the differential diagnosis between this entity, AD and frontotemporal dementia.
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Neuropathol. Appl. Neurobiol. · Feb 2011
ReviewReview: molecular genetics and pathology of hereditary small vessel diseases of the brain.
Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. ⋯ The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.
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Neuropathol. Appl. Neurobiol. · Feb 2011
ReviewReview: role of cerebral vessels in ischaemic injury of the brain.
This review discusses the pathological changes in the heart and vessels underlying brain ischaemic injury, with a major focus on atherosclerotic disease of the brain induced by lesions of the extracranial cervical and major intracranial arteries and small-vessel disease of the brain. The carotid bifurcation is the primary site for atherosclerotic changes, for which extensive clinical trials and pathological analyses on carotid endarterectomy specimens have been performed. Plaque rupture and erosion give rise to thrombus formation, which leads to brain ischaemic injury. ⋯ Small-vessel disease of the brain induces fibrinoid necrosis, microaneurysm, fibrohyalinosis, lipohyalinosis and microatheroma, changes commonly associated with hypertension. The acute hypertensive small-vessel changes organize to create segmental arterial disorganization and deep small infarcts when they escape from rupture. Some specific vascular diseases responsible for brain ischaemic injury are briefly reviewed also.